In this proposal we will use mouse models that have mutations in the Cell cycle gene loci. We are studying mechanisms of glucose tolerance and energy homeostasis by evaluating functions in different metabolic organs in mice harboring mutations in several cell cycle genes. The findings are revealing important role of Cdks and TGF-beta proteins in processes that modulate energy balance. We are employing tissue-specific conditional mice and transgenic mice to abalte or activate the expression of candidate cell cycle proteins using Cre-loxP technology. These mouse models are them charaterized to evalaute their glucose tolerance and energy expenditure phenotypes. Where appropriate we are challenging the mice with high-fat diet, exercise and/or cold exposure to further understand the role of cell cycle protein in energy metabolism via study of distinct glucose/insulin responsive tissues/cells.